Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.TM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. In addition to the natural fermentation products, mevastatin and lovastatin, there are a variety of analogs thereof, produced by microbial, enzymatic and synthetic techniques.
The naturally occurring compounds and their analogs have the following general structural formulae: ##STR2## wherein: R.sup.1 is hydrogen, C.sub.1-5 alkyl or C.sub.1-5 alkyl substituted with a member of the group consisting of phenyl, dimethylamino, or acetylamino; and
R* is ##STR3## wherein p0 Q is R.sup.3 --C-- or R.sup.3 --CH; R.sup.3 is H or OH or Q is --CHCH.sub.2 OH CH.sub.3 PA0 M is --CHR.sup.4, R.sup.4 is hydrogen or hydroxy; X is CR.sup.5 R.sup.6, O, S, or NH; R.sup.5 and R.sup.6 are H, OH, or OR.sup.7 where R.sup.7 represents a phosphoryl or acyl moiety; PA0 R.sup.2 is hydrogen or methyl; and a, b, c, and d represent single bonds, one of a, b, c or d represents a double bond, or both a and c or both b and d represent double bonds provided that when a is a double bond, Q is ##STR4## or C.dbd. and when d is a double bond, M is ##STR5## and H provided that when R.sup.5 or R.sup.6 is OH or OR.sup.7 or X is O, S, or NH, a, b, and c are single bonds.
U.S. Pat. No. 4,517,373 discloses hydroxy containing compounds represented by the above general formula wherein R* is ##STR6##
U.S. Pat. Nos. 4,537,859 and 4,448,979 also disclose hydroxy-containing compounds represented by the above general formula wherein R* is ##STR7##
These compounds are prepared by the action of certain microorganisms on the corresponding non-hydroxylated substrates. One such organism described in U.S. Pat. No. 4,537,859 is of the genus Nocardia.
U.K. Patent 2,075,013 discloses hydroxy containing compounds represented by the above general formula wherein R* is: ##STR8## wherein R.sup.1 is H or Me, and R.sup.2 is H or acyl.
U.S. patent application Ser. No. 254,525 filed Oct. 6, 1988 discloses 6-substituted compounds of the above general formula wherein R* is: ##STR9## wherein R is CH.sub.2 OH, CH.sub.2 OCR.sup.4, CO.sub.2 R.sup.7 or CNR.sup.8 R.sup.9 ; and R.sup.1, R.sup.4, R.sup.7, R.sup.8 and R.sup.9 are broadly defined organic moieties.
U.S. Pat. Nos. 4,604,472 and 4,733,003 disclose compounds of the above formula wherein R* is: ##STR10## wherein X represents a hydrogen atom or a 2-methylbutyryl group, Y represents a hydrogen atom or a methyl group and R.sup.1 and R.sup.2 are the same or different and each represents an oxygen atom or a group of formula .dbd.N--OR.sup.3 where R.sup.3 is a hydrogen or alkyl moiety.